Antibacterial activity of DL 473, a new semisynthetic rifamycin derivative.

The activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human monocytederived macrophages were determined. The MICs and MBCs of rifapentine for intracellular bacteria were twoto fourfold lower than those of rifampin. For extracellular bacteria, this difference was less noticeable. Nevertheless, the more favorable pharmacokinetics of rifapentine over rifampin was addressed in other experimental models. These models showed substantial differences after short pulsed exposures of the infected macrophages to the drugs and when the infected macrophages were exposed to changing drug concentrations that imitated the pharmacokinetic curves observed in blood. Once-a-week exposures to rifapentine concentrations equivalent to those attained in blood after one 600-mg dose resulted during the first week in a dramatic decline in the number of bacteria, and this decline was maintained at a minimal level for a period of four weeks. The results of this study have shown the suitability of rifapentine for intermittent-treatment regimens. The prolonged effect of rifapentine found in this study may be associated with high ratios of intracellular accumulation, which were four-to fivefold higher than those found for rifampin. Further studies on the intracellular distribution of rifamycins and on the sites of actual interaction between the drugs and bacteria residing in macrophages are necessary.The combined use of isoniazid, rifampin, and pyrazinamide provided the basis for a successful short course of tuberculosis therapy. The discovery of long-lasting rifamycins, particularly of rifapentine (RPT), created the possibility for intermittent drug regimens (5,7,18). In the early studies, RPT was reported to have an in vitro activity the same as or higher than that of rifampin (RMP) (19,20). Subsequent studies have shown that the broth-determined MICs of RPT were two-to threefold lower than those of RMP (8, 10). The elimination half-life of RPT in animals and humans was about five times longer than that of RMP, and the levels of RPT in plasma substantially exceeded the MICs for a period of up to 72 h after a single oral dose (1)(2)(3)12). The advantage of RPT over RMP has been shown in murine models (1,5,11,18). Besides its more favorable pharmacokinetic parameters in blood, RPT accumulates to higher concentrations than does RMP in polymorphonuclear leukocytes and macrophages (6,9,16).In anticipation of a controlled clinical trial for the comparison of RPT and RMP in the therapy of tuberculosis, the present study compares the potential activities of these rifamycins against extracellular and intracellular Mycobacterium tuberculosis. Inhibitory and bactericidal activities (MICs and MBCs) against intracellular bacteria in human monocyte-derived macrophages were determined and compared with MICs and MBCs against extracellular bacteria. The actual accumulation of these drugs in human monocytes was also determined. Special attention was given to the evaluation of the long-lasting effect of RPT after pulsed expo...

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Comparison of activities of rifapentine and rifampin against Mycobacterium tuberculosis residing in human macrophages

Mor

Simon

Mezo

et al. 1995

“…have been investigated for their activities against Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) in in vitro, macrophage, and animal models (1,3,8,10). In a similar attempt, the Chemical Pharmaceutical Research Institute, Sofia, Bulgaria, has developed a new rifamycin derivative, 3-(4-cinnamylpiperazinyl iminomethyl) rifamycin SV, which was called T9 (Fig.…”

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Antimycobacterial activity of a new rifamycin derivative, 3-(4-cinnamylpiperazinyl iminomethyl) rifamycin SV (T9)

Reddy

Nadadhur

Daneluzzi

et al. 1995

The antimycobacterial activities of a new rifampin (RIF) derivative, 3-(4-cinnamylpiperazinyl iminomethyl) rifamycin SV (T9), against 20 susceptible and multidrug-resistant strains of Mycobacterium tuberculosis and 20 Mycobacterium avium complex (MAC) strains were investigated. The radiometric MICs of T9 for M. tuberculosis were significantly lower than those of RIF. The MICs of T9 and RIF at which 90% of the RIF-susceptible strains were inhibited were <0.25 and <0.5 g/ml, respectively. Interestingly, T9 had lower MICs against some RIF-resistant M. tuberculosis strains. T9 had better activity against MAC strains, and the MIC at which 90% of the MAC strains were inhibited was <0.125 g/ml, and that of RIF was <2.0 g/ml. T9 also showed high in vitro bactericidal and intracellular activities which were significantly superior to those of RIF against both M. tuberculosis and MAC strains. More importantly, T9 showed excellent in vivo activity against M. tuberculosis H37Rv compared with that of RIF in both the lungs and spleens of C57BL/6 mice, indicating the potential therapeutic value of T9 in the treatment of mycobacterial infections.In recent years, several rifamycin derivatives (including rifapentine, rifabutin, and KRM-1648, etc.) have been investigated for their activities against Mycobacterium tuberculosis and Mycobacterium avium complex (MAC) in in vitro, macrophage, and animal models (1,3,8,10). In a similar attempt, the Chemical Pharmaceutical Research Institute, Sofia, Bulgaria, has developed a new rifamycin derivative, 3-(4-cinnamylpiperazinyl iminomethyl) rifamycin SV, which was called T9 (Fig. 1). Investigations conducted by the developers of the drug have indicated good therapeutic activity, lack of toxicity, and favorable pharmacokinetics and bioavailability in experimental animals (4, 5). In this communication we report the antimycobacterial activities of T9 against M. tuberculosis and MAC. MATERIALS AND METHODSDrugs. T9 was supplied by the Chemical Pharmaceutical Research Institute (NIHFI); rifampin (RIF) was purchased from Sigma Chemical Company (St. Louis, Mo.). For in vitro studies, stock solutions of the drugs were prepared in dimethyl sulfoxide and stored at Ϫ80ЊC. Required dilutions were made in distilled water for inoculation to BACTEC vials and for macrophage studies. For in vivo studies, the drugs were suspended in sterile distilled water containing 0.5% carboxymethyl cellulose. Drug suspensions were made every week and stored at Ϫ10ЊC until use.Mycobacteria. M. tuberculosis strains used in the study consisted of susceptible and multidrug-resistant (MDR) strains of M. tuberculosis. The sources of the strains and detailed drug susceptibility patterns have been described previously (8). M. avium strains used in the study were smooth, transparent colonial forms isolated from AIDS patients.Macrophages. Intracellular activity of T9 was determined with the J774A.1 mouse macrophage cell line, which was obtained from the American Type Culture Collection and maintained in Dulbecco's modified Eagle's m...

“…However, KRM-1648 was not efficacious in suppressing the progression of pulmonary lesions and the increase in bacterial loads at the sites of infection, including lungs and spleen, at the late phase of infection. This may imply some difficulty with chemotherapy for AIDSassociated MAC infection, even with KRM-1648 treatment, which has excellent in vitro and in vivo anti-MAC activities, as shown in the present study.Rifampin (RMP) and other rifarmycins, including rifabutin (RBT), rifapentine, and so on, are highly active against slowly growing mycobacteria, particularly Mycobacterium tuberculosis and some nontuberculous mycobacteria (1,3,5,7,14,18,24,28,29,36). However, they are not so excellent in their in vitro activity against M. avium complex (MAC) (5,19,28), supposedly because of the permeability barrier of the organisms (11,25).…”

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“…(RBT), rifapentine, and so on, are highly active against slowly growing mycobacteria, particularly Mycobacterium tuberculosis and some nontuberculous mycobacteria (1,3,5,7,14,18,24,28,29,36). However, they are not so excellent in their in vitro activity against M. avium complex (MAC) (5,19,28), supposedly because of the permeability barrier of the organisms (11,25).…”

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confidence: 99%

Chemotherapeutic efficacy of a newly synthesized benzoxazinorifamycin, KRM-1648, against Mycobacterium avium complex infection induced in mice

Tomioka

Saito

Sato

et al. 1992

Newly synthesized benzoxazinorifamycin, KRM-1648, was studied for its in vivo anti-Mycobacterium avium complex (MAC) activities. When the MICs were determined by the agar dilution method with Middlebrook 7H11 agar medium, KRM-1648 exhibited similarly potent in vitro antimicrobial activities against the MAC isolated from AIDS and non-AIDS patients, indicating possible usefulness of KRM-1648 against AIDSassociated MAC infections. KRM-1648 exhibited potent therapeutic activity against experimental murine infections induced by M. intracellulare N-260 (virulent strain) and N-478, which has much weaker virulence. Similarly, KRM-1648 exhibited an excellent therapeutic efficacy against M. intracelulare infection induced in NK-cell-deficient beige mice (as a plausible model for AIDS-associated MAC infection), in which a much more progressed state of gross lesions and bacterial loads at the sites of infection were observed. When the infected beige mice were killed at weeks 4 and 8, obvious therapeutic efficacy was seen on the basis of reduction in the incidence and degree of lung lesions and bacterial loads in the lungs and spleen with infections due to M. intracelulare N-241, N-256, and N-260. In this case, the efficacy was the highest in N-260 infection, followed by strain N-241. When mice were observed until infection-induced death, survival time of the infected beige mice was found to be prolonged by KRM treatment. However, KRM-1648 was not efficacious in suppressing the progression of pulmonary lesions and the increase in bacterial loads at the sites of infection, including lungs and spleen, at the late phase of infection. This may imply some difficulty with chemotherapy for AIDSassociated MAC infection, even with KRM-1648 treatment, which has excellent in vitro and in vivo anti-MAC activities, as shown in the present study.Rifampin (RMP) and other rifarmycins, including rifabutin (RBT), rifapentine, and so on, are highly active against slowly growing mycobacteria, particularly Mycobacterium tuberculosis and some nontuberculous mycobacteria (1,3,5,7,14,18,24,28,29,36). However, they are not so excellent in their in vitro activity against M. avium complex (MAC) (5,19,28), supposedly because of the permeability barrier of the organisms (11,25). Moreover, it is not known whether RMP and other rifamycins are really efficacious in the treatment of patients with MAC infections. Some investigators have reported that multidrug chemotherapy, including treatment with RMP, has been used in many cases of clinical management of AIDS-or non-AIDS-associated MAC patients with success (4, 6). In contrast, others have reported unavoidable difficulty in clinical control of MAC, even by using RMP combined with other drugs (36). For instance, Rosenzweig (27) reported that sustained conversion of sputum with such chemotherapy alone was achieved in only 41% of patients and, after a 6-month trial of drugs including RMP, 33% of the patients experienced relapse.Because rifamycin with a high in vitro anti-MAC activity and superior pharmacokin...